Abstract
The development of effective therapies inhibiting prostate cancer progression and metastasis may substantially impact prostate cancer mortality and potentially reduce the rates of invasive treatments by enhancing the safety of active surveillance strategies. Hepsin (HPN) is a cell surface serine protease amplified in a subset of human sarcomas (7.2%), as well as in ovarian (10%), lung adeno (5.4%), lung squamous cell (4.5%), adenoid cystic (5%), breast (2.6%), uterine (1.7%) and colon (1.4%) carcinomas. While HPN is not amplified in prostate cancer, it is one of the most prominently overexpressed genes in the majority of human prostate tumors and genetic experiments in mice indicate that Hepsin promotes prostate cancer metastasis, particularly metastasis to the bone marrow. We report here the development, analysis and animal trial of the small-molecule Hepsin inhibitor HepIn-13. Long-term exposure to HepIn-13 inhibited bone, liver and lung metastasis in a murine model of metastatic prostate cancer. These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.
Highlights
Prostate cancer is the most common nonskin cancer in American males [1]
Hepsin is prominently overexpressed in the majority of human prostate cancers and functional in vivo studies support a causal role for Hepsin in cancer progression [12, 18, 19]
We show here that HepIn-13 inhibits Hepsin and blocks prostate cancer metastasis
Summary
Prostate cancer is the most common nonskin cancer in American males [1]. While organ-confined prostate tumors are usually curable, metastatic prostate cancer is highly resistant to therapeutic intervention and almost uniformly fatal. The development of effective novel targeted therapies to inhibit prostate cancer metastasis could have a considerable impact on prostate cancer mortality. Hepsin (HPN) is one of the most upregulated genes in human prostate cancer and is overexpressed in up to 90% of prostate tumors with levels often increased >10 fold [2,3,4]. Hepsin increases early in prostate cancer initiation and its high levels are maintained throughout progression and metastasis [3,4,5,6]. Hepsin can cleave and activate pro-uPA, pro-HGF, Laminin332 and pro-MSP [9,10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
